This invention relates to a new class of penicillins (I) and their pharmaceutically acceptable salts and esters which are useful as antibiotics: ##STR3## wherein the stylized radical (hereafter referred to as R'): ##STR4## attached to the 6-amino nitrogen moiety of the penicillin (or ring analogue thereof) nucleus represents a mono- or polycyclic N-containing heterocyclic group; X is S, SO, CH.sub.2, or O; m is 0, 1 or 2;
R is, inter alia, hydrogen, substituted and unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkyl, heterocyclylalkenyl, aralkenyl, aralkyl, --NR.sub.2, COOR, CONR.sub.2, --OR or CN; R.sup.2 is H, or lower alkoxyl. The heterocyclic radical, R', is further defined below.
The compounds of the present invention are most conveniently isolated as the zwitterionic species demonstrated by structure I. This structure is the principal one and is utilized in the claims; however, one should be aware of other salt forms which are imposed by distinct, less preferred isolation procedures. Isolation from acidic solution provides salts which may be represented by the following structure: ##STR5## wherein Y is a pharmaceutically acceptable anion such as chloride, sulphate, acetate, propionate, citrate, tartrate or the like.
Isolation from basic, solution (aqueous, for example) yields salts which may be represented by the following structures; wherein equilibrium with the imino form is indicated: ##STR6## wherein M is an alkali or alkaline earth metal cation, for example, sodium, or potassium. Isolation from basic, non-aqueous solution such as dimethylformamide (DMF) in the presence of an amine NR.degree..sub.3 (R.degree. is, for example, loweralkyl) yields salts which may be represented by the following structure: ##STR7## The above structure assumes that NR.degree..sub.3 is a stronger base than the iminoheterocyclyl moiety, ##STR8##
This invention also relates to processes for the preparation of each compounds (I); pharmaceutical compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts and esters; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.